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Metabolism of lipids
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ketone bodies
CO2 + H2O
Transport of free fatty acid in the plasma
triacyl glycerol
fatty acid
Hormonsensitivelipase
ADIPOSE TISSUE
FFA
phospholipid synthesis
Ac-CoA
ketone bodies
oxidation
Ketone bodies CO2 + H2Ofatty acid
Phospholipid, triacylglycerolsynthesis
FREE FATTY ACID (FFA)
fatty acid-albumin
ORGANSskeletal muscle heart muscle kidney
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Composition of lipoproteins
cholesterol
Triacylglycerol, cholesterol-esther
phospholipid
Apoprotein
• Surface:
apoproteins
phospholipids
cholesterol
• Core components:
triacylglycerols
cholesterol-estherspolarapolar
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A-I, A-II, C-I, C-II, C-III, E
phospholipid, cholesterol-
esther50-5540-55HDL
B-100cholesterol-esther75-8020-25LDL
B-100, ETriacylglycerol
cholesterol-esther
80-8515-20IDL
B-100, C-I, C-II, C-III, ETriacylglycerol90-937-10VLDL
B-48, C-II, C-III, ETriacylglycerol98-991-2
Chylo-mikron(CM)
Apoproteinimportant lipidLipid
content(%)
Protein content
(%)DensityLipoprotein
Characteristics of lipoproteins
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Structure of cholesterol
Basic structure: sterol ring (ciklopentanoperhydrofenantren)
Hydrofobic, non-water soluble
70 % of it exits in cholesterol-esther form
1.2.
3.
4.
5.
6.
7.
8.
9.
10.
11.12.
13.
14. 15.
16.17.
18.
19.
20.
21. 22. 24. 27.
23. 25.
26.
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Role of cholesterol
• it can be found in all cell types
• origin:
exogen: (food intake)
endogen: intracellular de novo synthesis
• role:
regulation of membrane fuidity
precursor for steroid hormon synthesis
precursor for bile acid synthesis
precursor for vitamin D3
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3,3-dimethylallylpirophosphate
Synthesis of cholesterol I.
Acetoacetyl-CoATiolase HMG-CoA-
synthase HMG-CoA
Mevalonate-kinase
phosphomevalonate-kinaseMevalonate-
5-pirophosphodecarboxylase
5-phosphomevalonate5-pirophosphomevalonate3-izopentenyl-pirophosphate
Isomerase
HMG-CoA-reductase
2 NADPH+H+
2 NADP+
ATPADP
ADPATP
ADPATP
Mevalonate
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3-izopentenylpirophosphate
3,3-dimethylallylpirophosphate
Isomerase
Prenyl-transferase
Geranyl-pirophosphateFarnesyl-
pirofoszfát
Squalene
Squalene-2,3-epoxideLanosterol
Prenyl-transferase
3-izopentenylpirophosphate
Squalene-synthase
Squalene-monooxygenase
Squalene-epoxide-lanosterol-cyclase
2
NADPH+H+
NADP+
Synthesis of cholesterol II.
+
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Lanosterol
Cholesterol
Dihydrolanosterol
7-dehydrocholesterol
NADPH+H+NADP+
NAD+ NADH+H+
Synthesis of cholesterol III.
3-hydroxisteroid-24-reductase
3-hydroxisteroid-8, 7-isomerase
3-hydroxisteroid-7-reductase
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Regulation of cholesterol synthesis
HMG-CoA-reductase
Ac-CoA
Mevalonate
CHOLESTEROL
BILE ACIDS
CHOLESTEROL
Drugs (Statins)
GLUCAGON
KORTISOL
INSULIN
TRIJODOTIRONINE
EXOGEN CHOLESTEROL
chylomicron
Plasma
cholesterol(LDL)
+
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Introduction
Characteristics:
• formation from Acetyl-CoA
• water soluble molecules
• produced mainly by liver, less by
•alternative energy sources for peripherial tissues
Ketone bodies:
• concentration in blood stream < 0,2 mM
-hydroxi-butyrate acetoneacetoacetate
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Synthesis of ketone bodies
2 acetyl-CoACoA-SH Ac-CoA
+ H2OCoA-SH
HMG-CoA-synthase
Acetoacetyl-CoA 3-hydroxi-3-methyl-glutaryl-CoA
(HMG-CoA)
Acetil-CoA
HMG-CoA-liase
CO2NAD+ NADH+H+
-hydroxibutyrate-dehydrogenase
-hydroxi-butyrate acetoneacetoacetate
Tiolase
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Utilisation of ketone bodies
NAD+ NADH + H+
Succynyl-CoA
Succynate
2
CoA-SH
-hydroxi-butyrate Acetoacetate
Acetoacetyl-CoAAcetyl-CoA
Acetoacetate: succynyl-CoA
transferase
Tiolase2
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Utilisation of ketone bodies
acetoacetate
hydroxi-butyrate
TCA cycle
2 Ac-CoA
acetoacetyl-CoA
succynate
succynyl-CoAacetoacetate
hydroxi-butyrate
CoA-transferase
Peripheral tissues:
heart muscle
skeletal muscle
kidney
brain
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Utilisation of fatty acids
Tissues are not supported by fatty acids: nervous tissue
red blood cell
adrenal medulla
Fatty acids are predominant energy supply for heart and skeletalmuscle
Utilisation of fatty acids by tissues mainly depends on actual need
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Transport of fatty acids to mitochondria
CARNITINE CARRIER
Carnitine Acyl-carnitine
Acyl-carnitineCarnitine
Acyl-CoA
-oxidation
CoA – SH
MITOCHONDRIA
INNER MITOCHONDRIAL
MEMBRANE
CITOPLASM
Acyl-CoA
Fatty acidATP
AMP + PPi
CoA – SH
ACTIVATION
CoA – SH Carnitine-acyltransferase I.
Carnitine-acyltransferase II.
Malonyl-CoA
–
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Oxidation of Even numbered fatty acids – -oxidation
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Metabolism of propionyl-CoA
CH2 C S CoA
O
H3C
CH C S CoA
O
H3C
COO-
CH2 C S CoAO
CH2-OOC CH2
ATP
ADP + Pi
HCO3-
Propionyl-CoA-carboxylase
Methyl-malonil-CoA-mutázVitamin-B12
Succynyl-CoA
Methyl-malonyl-CoA
Propionyl-CoA
cofactor: biotin
cofactor: B12
Citric acid cycle
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Oxidation of fatty acids with „cis” conformation I.
C C S CoA
O
CCH2(CH2)nH3C
H H
1.4. 3. 2.
CH2 C S CoA
O
CCH2(CH2)nH3C
H
OH
CH2 C S CoA
O
CCH2(CH2)nH3C
OH
H-L-hydroxy-acyl-CoA
-D-hydroxy-acyl-CoA
cis-2-enoyl-CoAH2O
Hydratase
Epimerase
-oxidation
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C C S CoA
O
C CH2(CH2)nH3C
HH
1.4. 3. 2.
C C S CoA
O
CCH2(CH2)nH3C
H
H
1.2.3.4.
cis-3-enoyl-CoA
trans-2-enoyl-CoA
Izomerase
-oxidation
Oxidation of fatty acids with „cis” conformation II.
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Additional steps of oxidation of linolic acid (18:29,12)
CH2 C S CoA
O
C CH2(CH2)4H3C
HH
1.4. 3. 2.C5.
C C S CoA
O
C C(CH2)4H3C
HH
1.4. 3. 2.C5.
H
H
C C S CoA
O
C CH2(CH2)4H3C
H
1.4. 3. 2.CH2
H
C C S CoA
O
CH2 C(CH2)4H3C 1.4. 3. 2.CH25.
H
Htrans-2-enoyl-CoA
trans-3-enoyl-CoA
trans-2-cis4enoyl-CoA
trans4enoyl-CoA
NADPH+H+
NADP+
Isomerase
Reductase
Acyl-CoA-dehydrogenase
-oxidation
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Saturated fatty acids
• carbon chain and terminal carboxyl group
• the carbon chain does not contain any double bonds
• flexible, linear structure
• General structure:
short chain: n=2 – 5
middle chain: n=6 – 11
long chain: n=12 – 26
(CH2)xH3C COOHCH2 CH2 CH21.2.3.4.n.
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Unsaturated fatty acids
5,8,11,14 -6420Arachidonicacid
9,12,15 -3318Linolenicacid*
9,12 -6218Linoic acid*
9 -9118Oleic acid
018Stearic acid
9 -7116Palmitoleicacid
016Palmitic acid
Position of double bonds
Number of double bonds
Number of carbonsFatty acid
*: essential fatty acids
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Essential fatty acids
Linolsav: -6 zsírsav
Role:
• synthesis of eikozanoids
• synthesis of poli-unsaturated fatty acids taking part in formation of biological membranes
Occurence:
• linoic acid: plant oils
• linolenic acid: sea fish
Linolénsav: -3 zsírsav
Linoic acid
Linolenic acid
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Origin of components required for fatty acidsynthesis
Acetyl-CoA: from carbohydrate metabolism (reaction catalysed by pyruvate-dehydrogenase enzyme complex)
NADPH: direct oxidation of glucose
reaction catalysed by malic enzyme in cytoplasm
reaction catalysed by az isocitrate-dehydrogenase
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Transport of acetyl-CoA to the cytoplasm
MITOCHONDRIUM
Acetyl-CoA CITRATE
oxaloacetate
CITRATE Acetyl-CoA
ATP ADP + Pi
HS – CoA oxaloacetate
isocitrate
-ketoglutarate
ATP–
CYTOPLASMATP-citrate-liase
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Source of NADPH
oxaloacetate
Acetyl-CoA
Fatty acid synthesis
malate
pyruvate
NADH+H+ NAD+
NADPH+H+
NADP+
Malate-dehydrogenase
+ HCO3-
Malicenzyme
ATP-citrate-liase
citrate citrate
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de novo synthesis of fatty acids
• all fatty acids synthesised from palmitic acid
•Catalytic anzyme: fatty acid synthase
2 subunit – 7 different protein with biological activity
2 –SH-groups for binding of acyl- and acetyl groups in eachsubunits
ACP (acyl carrier protein): binding of 4’-foszfopantetheine
Enzymes:
acyl-transferase
malonyl-CoA-ACP-transzacylase (malonyl-transferase)
-ketoacyl-ACP-synthase (kondenzáló enzim)
enzymes redukáló enzimek
tioészteráz
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Model of fatty acid synthase
Acyl-transferase
Malonyl-transferase
Ketoacyl synthase
Reducing enzymes Thioesterase
DOMAIN I. DOMAIN II. DOMAIN III.
SUBUNIT I.
Ketoacyl synthase
Acyl-transferase
Malonyl-transferase
Reducing enzymesThioesterase SUBUNIT II.
SH
SH
ACP
ACP
SH
SH
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Synthesis of fatty acid
Ketoacylsynthase
Ketoacylsynthase
Ketoacylsynthase
Ketoacylsynthase
Ketoacylsynthase
S
O
CH3
C
SH SH
CH2
S
O
CH2
C
CH3
CH2
S
O
CH2
C
CH3
ACP ACP ACP ACPACP
S
O
CH2
C
COO-
S
O
CH2
C
C O
CH3
S
O
CH2
C
CH2
CH3
SH S
O
CH2
C
COO-
condensation reducing translocation next
malonyl-CoAcondensation
stepsCO2 CO2
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Reducing steps in fatty acid synthesis
CSACP
O
C CH3CH2
OAcetoacethyl-S-ACP
CHSACP
O
C CH3CH2
OH
-hidroxy-butiryl-ACP
CHSACP
O
C CH3CHCrotonil-S-ACP
CH2SACP
O
C CH3CH2Butiryl-S-ACP
NADPH + H+
NADP+
NADPH + H+
NADP+
ketoacyl-ACP-reductase
hidroxy-acyl-ACP-dehydratase
enoyl-ACP-reductase
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Regulation of fatty acid synthesis
R C S CoA
OHCO3
-+
ATP ADP+Pi
C S CoAO
CH2-OOC
Acetyl-CoA-carboxylase
Main step of fatty acid synthesis: acetyl-CoA-carboxylase
• Cofactor: biotin – binding of CO2 with usage of ATP
• Regulation: allosteric activator: citrate – it helps in formation of activepolimer
allosteric inhibitor: malonyl-CoA, palmitoyl-CoA – they inhibitthe formation of active polimer
transcription of the enzyme adapts to the fed-state of the body
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Characterisation of arachidonic acid
Arachidonicacid
COOH
synthesis precursors are linoleic and linolenic acids
2-acyl position of a glicerophospholipids is saturated by arachidonicacid
free arachidonic acid concentration of cytosol is very limited
Committed step of eicosanoid biosynthesis is deliberation of arachidonic acod from phospholipids
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Deliberation of arachidonic acid from phospholipids
1. Phospholipase A2 (PLA2)
a) high molecular weight PLA2
Specific for arachidonic acid
Increase in the intracellular Ca2+ concentration support itstranslocation to the plasma membrane
b) low molecular weight PLA2
Not specific for arachidonic acid
Glucocorticoids inhibit it
2. Phospholipase C (PLC) and DAG-lipase
Arachidonic acid deliberated from diacyl glycerol by DAG lipasewhich originated from TG by a PLC
platelets
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Oxidation of arachidonic acid in the cells
Arachidonic acid
Prostaglandins(PG)
Thromboxanes(Tx)
Hydroperoxieicosa-tetraenoic acids (HPETE)
Hydroxyeicosatetraenoicacids (HETE)
Leukotrienes (LT)
Epoxieicosa-tetraenoic acids (EET)
Lipoxins
Cyclooxygenase-pathway
Lipoxygenase-pathway
Cytochrom P450Epoxygenase-pathway
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Oxidation of arachidonic acid
Leukotrienes:LTA4, LTB4, LTC4,LTE4, LTF4, LXA4
15-LPO
PGH2
5-LPO
PLA2
PLC
Phosphatidyl choline Phosphatidyl inositol
DAG-lipase
Leukotrienes:LXA, LXB
Prosztaglandins:PGE2, PGD2, PGF2, PGA2, PGB2
PGH2
PGH2
COX
COXCOX
Prostacyclines:PGI2, PGF2
Thromboxanes:TXA2, TXB2
Arachidonic acid
Tx-synthase
Prostacycline-synthase
PG-synthse
DAG: diacyl-glycerol
COX: cyclooxygenase
Tx: thromboxane
LPO: lipoxygenase
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Arachidonic acid
PGG2
PG-hidro-peroxidase
PGI2
COX
PGH2
The cyclooxygenase-pathway
2 O2
PGE2
PGD2
PGF2
TxA2
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Pros
tacy
clin
synt
heta
se
Thromboxane-s
yntheta
se
PGH-PGE-izomerase
PGH-PDF-reductase
PGH-PGD-izomerase
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lipoxigenase
Arachidonicacid
5-HPETE
5-HETEdiHETE-derivatives
LTA4
LTB4
LTC4
glutathione
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O2
LT D4 LT E4 LT F4
Glu Gly
Glu
5-lipoxigenase
epoxihydrolase
gluthatione-S-transzferase
-glutamyl-transpeptidase dipeptidase
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Action of anti-inflammatory drugs
Membrane phospholipids
phospholipids
Arachidonicacid
Prostaglandinendoperoxids
Tx A2 prostaglandins
5-HPETE
LT A4
LT C4
LT D4
LT E45-HETE LT B4
cyclooxygenase
NSAIDPl: Aspirin
-
steroids-